The overall goal of this proposal is to evaluate the safety and therapeutic potential of in vivo blockade of interactions between PD-1 and its ligands PD-L1 and PD-L2 to enhance control of HIV/AIDS in the more than 40,000,000 HIV-infected people world wide using a SIV/macaque model. Our hypothesis is that blockade of PD-1: PD-1 ligand (PDL) inhibitory pathway can provide therapeutic benefit by eliciting cell-mediated immunity capable of providing better viral control than the functionally limited T cells characteristic of established SIV infections. Recent studies in mice chronically-infected with LCMV clearly demonstrate that the virus-specific CD8 and CD4 T cells upregulate expression of PD-1 following infection and a transient in vivo blockade of PD-1 or PD-L1 can enhance the magnitude and functional quality of these T cells and improve viral control. Subsequently, studies in HIV-infected people demonstrate that HIV-specific CD8 and CD4 T cells also upregulate expression of PD-1 and in vitro blockade of PD-1 or PD-L1 enhances the proliferative capacity of these cells. More recently, studies from our laboratory as well as Dr. Koup's laboratory demonstrate similar phenomena in SIV-infected macaques. These results clearly demonstrate that the PD-1: PDL inhibitory pathway is operational during chronic HIV/SIV infection. Thus, in vivo blockade of the interactions of PD-1 with its ligands may be able to enhance the control of immunodeficiency virus infections by increasing the magnitude and functional quality of virus-specific T cells and might represent a new and powerful therapy for the control of HIV/AIDS. There is a serious need to optimize and evaluate the safety and therapeutic potential of in vivo blockade in animal models before this approach is tested in HIV-infected humans. Our preliminary studies demonstrate that it is safe to infuse humanized anti-PD-1 Ab into normal rhesus macaques. In our specific aim 1, we will evaluate the safety and therapeutic potential of in vivo blockade during the chronic phase (weeks 16-20) of SIV251 infection. Both, anti-PD-1 and PD-L1 antibodies will be tested. In our specific 2, we will evaluate the therapeutic potential of in vivo blockade in macaques that had been infected with SIV and treated with anti-retroviral therapy (ART). Blocking will be done immediately following the interruption of ART. During these experiments we will evaluate the magnitude and functional quality of SIV- specific cellular and humoral immunity in blood and at the intestinal mucosa to determine the effects of blockade on T cell and Ab responses and their role in viral control. These experiments will also study the temporal expression of PD-1, PD-L1 and PD-L2 on antigen presenting cells, T cells, B cells and virus-infected cells to further understand how the SIV infection modulates the expression of these molecules and the relationship between the expression of these molecules and viral control. Our goal is to reduce the set point viremia at least by 50-100 fold. In HIV-infected humans a 10-fold reduction in plasma viremia reduces the death rate from 50% to 5% and prolongs the survival time from less than 5 years to greater than 10 years.